Key Points

This phase III, randomized placebo-controlled study found that the drug donepezil, commonly used to treat cognitive symptoms of Alzheimer’s disease, was associated with significantly improved cognitive function among people who had received brain irradiation and who were at least six months post radiation treatment with no evidence of tumors.

The study also found that when study participants were separated out by pre-treatment cognitive scores, patients who had the relatively lowest scores before beginning donepezil showed significantly greater improvement in overall cognitive ability, immediate recall, delayed recall, attention, visual-motor skills, and motor speed and dexterity, compared with people who had higher pre-treatment scores.

This is the first study that has treated brain-irradiation induced cognitive impairment with a drug used for another disease population.

By Shira Klapper, Senior Writer/Editor

Brain irradiation for primary and metastatic brain tumors has long been known to cause neurotoxic effects, including cognitive impairments. Among the 200,000 people yearly who undergo whole-brain irradiation (WBI) and the 15,000 who undergo partial-brain irradiation (PBI), 50 to 90% will develop impairments primarily in the realms of executive function, learning, memory, mood, and energy level.

Over the years, clinicians and researchers have observed that the cognitive symptoms experienced by patients who receive WBI or PBI are similar to those experienced by people with Alzheimer’s disease. Based on these similarities, a team of researchers from multiple cancer centers across the United States carried out a phase III, randomized placebo-controlled study to see what would happen if donepezil, a drug commonly used to treat cognitive symptoms in Alzheimer’s disease, was given to patients who had undergone brain irradiation in the last six months or more and had evidence of tumors.

The study, “Donepezil for Irradiated Brain Tumor Survivors: A Phase III Randomized Placebo-Controlled Clinical Trial,” published in the Journal of Clinical Oncology (JCO) online, ahead of print, April 20, found that patients who received donepezil showed significantly greater improvement in the domains of memory and motor speed and dexterity, compared with the placebo group. In addition, when study participants were separated out by pre-treatment cognitive scores, the study found that patients who had the relatively lowest scores before beginning donepezil showed the most significant gains in overall cognitive ability, immediate recall, delayed recall, attention, visual-motor skills, and motor speed and dexterity, compared with people who had higher pre-treatment scores.

Commenting on these findings, study coauthor Edward G. Shaw, MD, MA, said, “This is the first study that has used a drug that has worked in another disease for this particular irradiated brain tumor survivor population. We knew that donepezil was a safe drug since it has been given to thousands of patients with Alzheimer’s disease and other dementias. What we believe is that radiation, and likely chemotherapy as well, essentially ages the brain 20 years beyond the person’s biological age. So, I think this study is a step forward for the field in that it opens the possibility of using other drugs that are used for dementia in people who have radiation-induced cognitive dysfunction.” Dr. Shaw also stated that in light of the finding that those with lower pre-treatment scores showed the most significant improvement, he and his colleagues will likely next study the effects of donepezil specifically on this population.

Improving cognitive ability by targeting acetylcholine

Dr. Shaw explained how donepezil might improve brain function.

“We hypothesized that radiation-induced neuronal injury causes a deficiency in acetylcholine, a nerve transmitter critical for memory and learning. And we know that for people with Alzheimer’s disease, donepezil increases the acetylcholine level in their brains and there’s some data suggesting it might even slow the progression of the Alzheimer’s.”

For the JCO study, patients randomized to the donepezil group received 5 milligrams (mg) of the drug for six weeks, followed by 10 mg of the drug for the next 18 weeks. Before beginning treatment, all 198 patients underwent testing across six domains: memory, attention, language, visual-motor, verbal fluency, and executive function. These scores were then aggregated into an overall, composite score.

The advantage of multidisciplinary research

For Dr. Shaw, one of the study’s main strengths is that it shows the strides that can be made when researchers from across disciplines work together.

“I think from a five or ten thousand foot view, part of the importance of our study is it that it represents a collaboration that involved laboratory researchers in radiation biology and neurobiology, clinicians from medical and radiation oncology as well as researchers from psychiatry and behavioral medicine, Wake Forest’s Cancer Center, Brain Tumor Center, and Alzheimer’s Center. By bringing everyone together with this inter and multidisciplinary approach, we can try to find answers for each of our research questions.”